Apparatus for synthesis of multiple organic compounds with pinch valve block

ABSTRACT

The simultaneous synthesis of diverse organic compounds is performed in stackable modules which are moveable among nesting sites located on work station platform. The reactor module includes a block adapted to receive an array of tube-like reactor vessels. The vessels are sized to optionally accept porus polyethelyene microcannisters with radio frequency transmitter tags. Each vessel has a bottom port connected to an outlet tube. A valve block located below the reactor vessels simultaneously controls discharge through the outlet tubes. The valves block includes plates with aligned, relatively moveable sets of rib surfaces which act through Teflon encapsulated silicone O-ring cord sections to simultaneously close rows of outlet tubes. By first utilizing reactor vessels in one set of 48 positions, out of the possible 52 reactor vessel positions in the reactor block, and then utilizing reactor vessels in the other set of 48 positions and shifting the relative position of the collection plate, a single reactor can be employed to discharge into all of the wells of a standard 96 well microtiter collection plate. The apparatus can be used to perform the entire synthesis or only the final cleavage step of radio frequency tagged synthesis.

This is a division of copending application Ser. No. 08/935,037, filedSep. 22, 1997.

The present invention relates to apparatus for combinatorial drugresearch to be used in the simultaneous parallel solid and solutionphase synthesis of large numbers of diverse organic compounds or for thefinal cleavage step of radio frequency tagged synthesis and moreparticularly to a modular apparatus designed for such purposes whichemploys a unique pinch valve block, which includes reactor vesselscapable of receiving porus polyethylene microcannisters with radiofrequency transmitter tags and which can be used to discharge into allof the wells of a standard microtiter plate.

Efficient testing of organic compounds in the modern pharmaceuticallaboratory requires the synthesis of large numbers of diverse organicmolecules in an automated and high speed manner.

The apparatus of the present invention is designed for use in such asystem, particularly one which employs solid phase synthesis techniques.It is useful in performing the entire synthesis or for performing onlythe final cleavage step of radio frequency tagged synthesis.

During the course of the synthesis, various operations must be performedon the samples, including reagent introduction and removal, agitation,washing, and compound removal by cleavage from a resin support. Precisecontrol of temperature, pressure and atmospheric gas mixtures may berequired at various stages. These operations are standard and can beperformed at task specific work stations which have been designed ormodified for use with one or more reactors.

Over the last few years, a number of different systems have beendeveloped to produce libraries of large numbers of specific types oforganic molecules, such as polynucleotides. However, the usefullness ofsuch systems tends to be limited to the particular type of molecule thesystem was designed to produce. Our invention is much more general inapplication. It can be used to synthesize all types of organic compoundsincluding those used in pharmaceutical research, the study of DNA,protein chemistry, immunology, pharmacology or biotechnology.

Aside from the lack of versatility, existing equipment for automatedorganic synthesis tends to be large and heavy, as well as very expensiveto fabricate and operate. Known automated systems also tend to be quitecomplex, requiring equipment which is limited as to flexibility, speed,and the number and amount of compounds which can as be synthesized. Aswill become apparent, our system has a simple, elegant design. It isrelatively inexpensive to fabricate and operate. However, it isextremely flexible and is capable of producing large numbers and amountsof all types of organic compounds in a high speed, automated manner. Itis smaller in size than comparable equipment, permitting more reactorsto be used at one time at a work station and it is lighter, therebyfacilitating movement of the apparatus between work stations with lesseffort.

One system of which we are aware was developed for use at ZenecaPharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UnitedKingdom. That system is built around an XP Zymate laboratory robot(Zymark Corporation, Hopkinton, Mass.). The robot arm is situated in themiddle of a plurality of stationary work stations arranged in a circle.The arm is programmed to move one or more tube racks from one station toanother. However, the Zeneca system has a small throughput capability,as the number of tube racks which can be handled at one time is limited.

An automated peptide synthesizer developed for Chiron Corporation ofEmeryville, Calif., which has similar limitations, is described byRonald N. Zukerman, Janice M. Kerr, Michael A. Siani and Steven C.Banville in an article which appeared in the International Journal ofPeptide and Protein Research, Vol. 40, 1992, pages 497-506 entitled“Design, Construction and Application of a Fully Automated EquimolarPeptide Mixture Synthesizer”. See also U.S. Pat. No. 5,240,680 issuedAug. 31, 1993 to Zuckermann and Banville and U.S. Pat. No. 5,252,296issued Oct. 12, 1993 to Zukerman et al. entitled “Method and ApparatusFor Biopolymer Synthesis”.

Another approach was developed at Takeda Chemical Industries, Ltd. andis described in an article published in the Journal of AutomaticChemistry, Vol. 11, No. 5 (Sept.-Oct. 1989) pp. 212-220 by NobuyoshiHayashi, Tobru Sugawara, Motoaki Shintani and Shinji Kato entitled“Computer-assisted Automatic Synthesis II. Development of a FullyAutomated Apparatus for Preparing Substituted N- (carboxyalkyl AminoAcids”. The Takeda System includes a plurality of stationary units whichare computer controlled. The reactor unit includes only two reactionflasks. A plurality of computer controlled solenoid values regulate theinput flow from the reactant supply unit and wash solvent supply unit aswell as output to the purification unit, exhaust and drainage unit.Sensors and electrodes feed information back to the computer. Thatsystem is complex, costly and inflexible. It is also very limited withrespect to the number of compounds which can be synthesized.

A more flexible approach has been suggested by the Parke-DavisPharmaceutical Research Division of Warner-Lambert, as described bySheila Hobbs DeWitt et al. in Proc. National Academy of Science, USA,Vol. 90, pp. 6909-6913 Aug. 1993 and in the ISLAR '93 Proceedings. Thatsystem employs a Tecan robotic sample processor. A manifold of gasdispersion tubes are employed in combination with glass vials. The glassfruits of the tubes contain the solid support during reactions. However,like many prior art systems, in this apparatus, samples from thereaction tubes must be removed from above, using a modified needle as aprobe. There is no facility for removal from the bottoms of the tubes.Accordingly, obtaining product from the reactor vessels in theParke-Davis system is awkward and time consuming.

U.S. Pat. No. 5,472,672 issued Dec. 5, 1995 to Thomas Brennan, entitled“Apparatus and Method for Polymer Synthesis Using Arrays”, teaches theuse of an automated system in which a transport mechanism is used tomove a base having an array of reactor wells in conveyor belt fashionfrom work station to work station. Sample removal is performed bycreating a pressure differential between the ends of the wells. Asidefrom the difficulties with regard to discharge, this system is complexand lacks flexibility.

We are also aware of system designed by the Ontogen Corporation ofCarlsbad, Calif. 92009 as disclosed by John Cargill and Romaine Maiefskiin Laboratory Robotics and Automation, Vol. 6 pp. 139-147 in an articleentitled “Automated Combinatorial Chemistry on Solid Phase” anddisclosed in U.S. Pat. No. 5,609,826 entitled “Methods and Apparatus forthe Generation of Chemical Libraries” issued Mar. 11, 1997 to JohnCargill and Romaine Maiefski. The system disclosed in the article andpatent utilizes a reactor block having an array of reactor vessels. Theblock is moved along an assembly line of work stations under computercontrol.

The Ontogen apparatus disclosed in the above mentioned article andpatent has a number of shortcomings. It is highly complex and expensive.It does not include any valving structure capable of regulating thefluid discharge from the reactor chambers. Instead, it depends uponpressure differential to cause discharge through ε-shaped trap tubeswhich snap into a fitting on the bottom of each reaction vessel. Thistakes up a lot of room, preventing the dense packing of the reactorvessels. It also makes product removal awkward.

Because the reactor vessels disclosed in the article and patent cannotbe densely packed, mirror image reactors are required in the Ontogensystem to discharge into all of the densely packed wells of a standardmicrotiter plate. As described in U.S. Pat. No. 5,609,826, two differentreactor configurations, each capable of receiving a set of 48 reactionvessels, are required to deposit directly into all 96 of the microtiterwells.

Reactor vessels of the type commonly used in the art are not adapted toreceive commercially available porus polyethelene microcannisters. As isdisclosed in the literature noted below, such microcannisters can beradio frequency transmitter tagged for automated tracking. Hence, itwould be very advantageous to have a reactor which could deposit intoall the microtiter wells and still utilize reactor vessels capable ofreceiving commercially available microcannisters.

International Publication Number WO 97/10896 under the PatentCooperation Treaty published on Mar. 27, 1997 teaches apparatus forsimultaneous solid phase chemical synthesis developed by BerlexLaboratories, Inc. of Richmond, Calif. The Berlex equipment utilizes amanifold valve block including a plurality of aligned valve insertswhich are controlled by valve stems. The stems are rotated by hydrauliccylinders positioned on either side of the manifold. The Berlexapparatus accommodates 96 reactor vessels at one time in a denselypacked array. However, the reactor vessels cannot receive porousmicrocannisters with radio frequency tags. Moreover, this reactorrequires a specially designed solvent delivery system.

Personnel at Bristol-Myers Squibb Company of Princeton, N.J. 08543developed an earlier version of the present apparatus designed for usein the simultaneous synthesis of diverse organic compounds. Like thepresent invention, it consisted of stackable modules which are movableamong nesting sites located on work station platforms. The reactormodule in that version includes a heat transfer block adapted to receivean array of reactor vessels. The reactor vessels are in the form ofsolid phase extraction cartridges without sorbent. Each has a bottomoutlet port. A plurality of separate valves arranged in rows are locatedbelow the vessels. The values consist of stopcocks which aregang-controlled to regulate the discharge from the reactor vessel outletports into aligned channels, each formed by a pair of threated Leur tipadapters. The reactor module is situated over a discharge module. Theinlet openings in the discharge module are adapted to accept thethreaded ends of the Leur tip adapters. The discharge module consists ofa multi-well collector block or a drain block. A solvent introductionmodule, which includes a pressure plate having an array of openings anda septum, is received over the reactor module. The downwardly projectingrim defining each pressure plate opening cooperates with the septum toengaged the mouth of the aligned reactor vessel to maintain a fluidtight seal.

Although that apparatus was a vast improvement over the prior artsystems, it still had some disadvantages. For example, the apparatus wasstill relatively large and has connectors and levers extending outwardlyfrom the sides, allowing only two reactors to fit under a standard fumehood at one time. Each reactor weighed about 18 pounds and was costly tofabricate. Thus, improvement in the areas of size, weight and cost arepossible. A more elegant valve system, with fewer moving parts, is alsodesirable. Provision for receiving commercially available porousmicro-cannisters with radio frequency transmitter tags for automatedencoding in the reactor vessels would be extremely advantageous.Moreover, a structure which could accommodate standard microtiter platesor blocks for specimen collection would be an important advance.Improvements in these areas are embodied in the present invention.

Our approach to the automation problem in this invention is to employmodules of simplified design and construction which can be readilyarranged in sets to perform the required operations and which are lightin weight so as to be easily moveable among nest sites at standard workstations. This permits the greatest amount of flexibility at the leastcost. Due to more compact design, more reactors can be assembled andemployed at one time by creating multiple nest sites at a single workstation, such as an orbital shaker. For time consuming operations,several work stations can be in use simultaneously, to permit parallelflow of reactors and therefore eliminate bottlenecks. For less timeconsuming operations, fewer work stations can be used, as long as theflow of reactors is not impeded. Because the reactors are lighter inweight, they are easier to transport. Accordingly, maximum throughput isachieved with minimum investment.

In addition, the apparatus of the present invention is designed topermit sample removal from the bottom of the reactor vessels as in theearlier version of the Bristol-Myers Squibb equipment. However, unlikethe earlier equipment system, the present invention employs simplifiedvalving in the form of a unique pitch valve block located beneath thereactor block. The valve block includes plates with sets of aligned,relatively moveable ribs. Each rib set is aligned with the outlet tubesassociated with a different row of reactor vessels. Movement of the ribsurfaces causes force to be applied to the outlet tubes through Telfonencapsulated silicone O-ring cord section situated between one ribsurface and the adjacent outlet tubes, such that the tubes aresimultaneously closed (pinched) without crushing or damaging the tubewalls. As a result, the tube walls will reliably resume their originalopen condition each time the force is released.

The apparatus of the present invention includes a reactor block, locatedabove the valve block, which accepts an array of reactor vessels. Thevessels may be any plastic or glass tube with a bottom port, such as astandard solid phase extraction cartridge without solvent. However, thereactor vessels are preferably designed to receive porus polyethelenemicrocannisters provided with radio frequency transmitter tags forautomated tracking. The apparatus can be used for the entire synthesisor only the final cleavage step in radio frequency tagged synthesis, asdesired.

The reactor module is adapted to mount over a discharge module. Thedischarge module may consist of a collection block with an array ofwells for collection tubes or vessels. Preferably, it takes the form ofa 96 well microtiter block of standard size and dimension. If thereactor vessels are large enough to accept commercially available porusmicrocannisters, they may be too large to permit them to be packedtightly enough to discharge into all of the 96 wells of a standardmicrotiter block at once. A funneling device could be interposed betweenthe valve block and the microtiter plate to direct the discharge fromthe reactor vessels into the wells of the plate. However, such a deviceis bulky and expensive to fabricate. Alternatively, as in the Ontogensystem mentioned above and disclosed in U.S. Pat. No. 5,609,826, mirrorimage reactors (referred to as type “A” and type “B”) could employed,each capable of holding 48 reactor vessels and discharging into adifferent set of 48 wells in the 96 well microtiter plate.

Our system overcomes the costs and problems of requiring an interposedfunneling device or having two reactor configurations by employing asingle reactor block with 52 possible reactor vessel positions, insteadof the conventional 48. Either one of two different sets (referred to as“odd” or “even”) of 48 positions out of the possible 52 positions can beselected for use. By shifting the position of the reactor block relativeto the microtiter plate, discharge into either the odd or even well setin the microtiter plate can be achieved.

Internal vertical supports are employed to facilitate alignment of theblocks as the reactor module sets are formed. The supports each have aplurality of different levels. Different blocks are designed to rest ondifferent levels. In this way, different reactor configurations areeasily formed. For example, reactors with or without temperature controlblocks can be assembled. Simple nesting brackets with chamfered surfacesmake installation of the reactors on the work stations a quick and easytask.

Since the modifications to standard work stations to accept the reactorsof the present invention are simple and inexpensive to make, little timeor cost is involved in converting a conventional laboratory for use withthe system of present invention. This dramatically increases the speedof the set up of a facility to perform the synthesis process, ascustomized work stations, specialized computers and complex interfacesare not required.

It is, therefore, a prime object of the present invention to provideapparatus for the synthesis of multiple organic compounds which ismechanically simple, small in size, light in weight, relativelyinexpensive to construct, does not require extensive set up time, isextremely flexible and has high throughput.

It is another object of the present invention to provide apparatus forthe synthesis of multiple organic compounds which consists of aplurality of stackable modules adapted to be moved as a unit among nestsites on work station platforms.

It is another object of the present invention to provide apparatus forthe synthesis of multiple organic compounds which can be used forperforming the entire synthesis or only the final cleavage step of radiofrequency tagged synthesis.

It is another object of the present invention to provide apparatus forthe synthesis of multiple organic compounds which includes a multiplevalve block in which sets of aligned ribs of relatively moveable platesact through Teflon encapsulated silicone O-ring cord sections to closerows of outlet tubes to regulate the discharge from the reactor vesselports.

It is another object of the present invention to provide apparatus forthe synthesis of multiple organic compounds which is compatible for usewith a standard 96 well microtiter collection plate where a singleconfiguration reactor block with 52 reactor vessel positions can beemployed to discharge into either the even or the “odd” 48 well sets ofthe plate by shifting the relative position of the microtiter plate.

It is another object of the present invention to provide apparatus forthe synthesis of multiple organic compounds which utilizes reactorvessels adapted to receive porus microcannisters with radio frequencytransmitter tags.

In accordance with one aspect of the present invention, apparatus usefulfor the synthesis of multiple organic compounds is provided. Theapparatus is adapted to receive an array of individual dual reactorvessels. Each vessel has a port connected to an outlet tube. Valve meanssimultaneously regulate the discharge from the vessels through theoutlet tubes. The valve means includes first and second relativelymoveable surfaces between which the outlet tubes extend. Resilient meansare interposed between one of the surfaces and the outlet tubes.Relative movement of the surfaces causes force to be applied through theresilient means to close the outlet tubes.

The valve surfaces are the surfaces of ribs located on relativelymoveable plates. The resilient means preferably takes the form of Teflonencapsulated silicone O-ring cord, cut in sections and situated adjacentone of the rib surfaces. The rib surface adjacent the cord is shaped tocorrespond to the shape of the cord. More specifically, it has anarcuate shape which serves to maintain the cord section in properposition. The ends of one of the plates have openings through which theresilient means can be inserted so as to be received between the ribs.

The valve means is located below the reactor vessels. Below the valvemeans is situated the collection block. The collection block has anarray of wells. A plurality of collection vessels are adapted to bereceived in the wells.

The collection block is capable of receiving 2× number of collectionvessels. The apparatus is adapted to receive X number of reactor vesselsin Y number of possible positions, where Y is a number larger than X.The collection block can be received in one of two positions relative tothe reactor block.

The reactor vessels may receive porus polyethylene microcannisters withradio frequency transmitter tags. Multi-level component internal supportand alignment means are provided.

In accordance with another object of the present invention, valve meansare provided for the simultaneous regulation of the discharge throughoutlet tubes connected to the ports of reactor vessels received in anapparatus for the synthesis of multiple organic compounds. The valvemeans includes first and second aligned, relatively moveable surfacesbetween which the outlet tubes extend. Resilient means are interposedbetween one of the surfaces and the outlet tubes. Relative movement ofthe surfaces causes force to be applied through the resilient means toclose the oulet tubes.

The surfaces form portions of plates, and more particularly ribs onplates. The resilient means preferably comprise Teflon encapsulatedsilicone O-ring cord sections. One of the rib surfaces is shaped tocorrespond to the arcuate shape of the outer surface of the cord.

In accordance with another aspect of the present invention, apparatususeful for the synthesis of multiple organic compounds is provided. Theapparatus includes means adapted to receive an array of X number ofindividual reactor vessels, in at least Y number of different positions,where Y is a number greater than X. Each of the vessels has a portconnected to an outlet tube. Collection means are provided with an arrayof 2× number of collection vessels. Means are provided for shifting theposition of the collection means relative to the vessel receiving means.By first selecting one and then the other set of X number of reactorvessels of the possible Y number of positions for use, and shifting theposition of the collection means between uses, each of the 2× number ofcollection vessels can receive discharge from the outlet tubes.

The collection means preferably comprises a standard 96 well microtiterplate. The number X equal 48. The number Y equal 52. Each of the vesselsis adapted to optionally receive a porus polyethylene miocrocannisterwith a radio frequency transmitter tag.

Valve means are interposed between the reactor vessels and thecollection means for simultaneously regulating the discharge through theoutlet tubes.

In accordance with another aspect of the present invention, apparatususeful to the synthesis of multiple organic compounds is provided. Theapparatus includes means for receiving an array of tube-like reactorvessels, a plurality of reactor vessels and optionally a porouspolyethelyne microcannister with a radio frequency transmitter tag foreach vessel. Each of the vessels is adapted to receive a poruspolyethelene microcannister with a radio frequency transmitter tag.

The vessel receiving means is capable of receiving X number of reactorvessels in Y number of wells, where Y is a number is greater than X. Theapparatus also includes collection means having 2× number of collectionwells. Each of the reactor vessels has a port connected to an outlettube. Valve means are provided for simultaneously regulating thedischarge of fluids through the outlet tubes into the collection wells.

The valve means includes first and second aligned, relatively moveablesurfaces between which the outlet tubes extend. Resilient means areinterposed between one of the surfaces and the outlet tubes. Relativemovement of the surfaces causes force to be applied through theresilient means to close the outlet tubes.

Preferably, one of the surfaces has an arcuate shape corresponding tothe shape of the exterior of the resilient means. This maintains theresilient means in proper position.

In accordance with another aspect of the present invention, apparatususeful for the synthesis of multiple organic compounds is provided,including a plurality of functional components stackable in differentconfigurations to form the apparatus. Multi-level means cooperate withthe components to align them. The alignment means is adapted to bemounted on one of the components. It has a first level adapted tosupport a second component and a second level adapted to support a thirdcomponent. The levels are defined by different sections of the alignmentmeans.

The components include a valve block. The alignment means is mounted onthe valve block.

The second component may include a temperature control block. A pressureplate is used in conjunction with the temperature control block.

The third component may including an alignment plate. The pressure plateis situated above the alignment plate.

The alignment means also includes a bullet nose shaped section on thetop level. This section facilitates assembly of the blocks.

The alignment means comprises a standoff. Preferably, the alignmentmeans includes four standoffs.

To these and other objects as may hereinafter appear, the presentinvention relates to apparatus for the synthesis of multiple organiccompounds with a pinch valve block, as set forth in detail in thefollowing specification and recited in the annexed claims, takentogether with the accompanying drawings, wherein like numerals refer tolike parts and in which:

FIG. 1 is an isometric view of a first configuration of the apparatus ofthe present invention including a temperature control block and showingthe collection block in exploded position;

FIG. 2 is an isometric view of a second configuration of the apparatusof the present invention without the temperature control block and withthe collection block in exploded position;

FIG. 3 is an exploded isometric view of the reactor block and valveblock of the apparatus of the apparatus of the present invention;

FIG. 4 is an exploded isometric view of the components of the valveblock;

FIG. 5 is a top cross-sectional view of the valve block, shown in theopen state;

FIG. 6 is an enlarged side cross-sectional view of the valve block takenalong line 6—6 of FIG. 5 showing the reactor block with the temperaturecontrol block;

FIG. 7 is a top cross-sectional view of the valve block, shown in theclosed state;

FIG. 8 is an enlarged cross-sectional view taken along line 8—8 of FIG.7;

FIG. 9 is an enlarged exploded side cross-sectional view of a portion ofthe plates and slide of the valve block;

FIG. 10 is a view similar to FIG. 6 showing an enlarged sidecross-sectional view of the valve block showing the reactor blockwithout the temperature control block;

FIG. 11 is a schematic representation of a first set the selectedreactor vessel wells and the set of collection wells with which theyalign;

FIG. 12 is a schematic representation of the second set of the selectedreactor vessel wells and the other set of collection wells with whichthey align;

FIG. 13 is a side cross-sectional view of the collection plate andvacuum adapter in the first relative position; and

FIG. 14 is a view similar to FIG. 13, showing the collection plate andvacuum adapter in the second relative position.

The apparatus of the present invention relates to a modular system forthe synthesis of diverse organic compounds in which components in theform of blocks and/or plates are stacked to form reactors which can bemoved among work stations to perform various steps in the synthesis. Atypical reactor consists of a reactor block, generally designated A,which is adapted to retain a plurality of tube-like reactor vessels 10.Block A may include an optional temperature control block, generallydesignated B, as shown in FIG. 1. Reactor Block A is situated above avalve block, generally designated C, which controls the discharge fromreactor vessels 10 into the collection vessels situated in the wells 12of a microtiter plate which forms a portion of a collection block,generally designated D.

Reactor block A includes a pressure plate 14 with a septum 16 situatedadjacent its undersurface. Pressure plate 14 has an array of relativelysmall openings 17, one for each vessel 10. Openings 17 permit the needleof a syringe to be inserted into the aligned reactor vessel, through theseptum, to introduce liquids into the vessel. When the temperaturecontrol block B is absent, as shown in FIG. 2, an alignment plate 18 issituated below septum 16. Alignment plate 18 has an array of openings 19each of which receives a reactor vessel 10 so as to retain the vesselsin the correct position relative to the pressure plate. Pressure plate14 is spaced from valve block C so as to permit a plurality of reactorvessels 10 to the situated therebetween.

Four multi-level alignment standoffs 20 are provided to retain thecomponents in proper alignment. Standoffs 20 are mounted on valve blockC, at each corner of the apparatus. Each standoff 20 has a lower, largerdiameter section 22, an intermediate, mid-sized diameter section 24 anda top, bullet shaped section 26. Temperature control block B, when used(FIG. 1), rests on lower section 22.

When block B is not used (FIG. 2 ), alignment plate 18 rests on theintermediate sections 24 of the standoffs. Alignment plate 18 isprovided with four holes 28 (FIG. 3). Holes 28 receive the top sections26 of standoff 20. Thus, plate 18 is spaced from the top surface of thevalve block C by the combined height of sections 22 and 24.

Pressure plate 14 also has four holes 30, somewhat smaller than holes28, which receives bullet shaped sections 26 of standoffs 20. Thepressure plate sits over the septum and hence is spaced above the topsurfaces of sections 24 of the standoffs. It rests on the rims of thereactor vessels 10, with the septum 16 situated there between (FIG. 10).Clamp brackets 37, located at either end of the unit, retain pressureplate 14. The bullet shape of sections 26 of standoffs 20 facilitatepositioning of the plates.

A pair of side latches 32 are mounted on latch pivot blocks 34 locatedon each side of the top surface of valve block C. Each latch has firstand second slots 36, 38 adapted to engage screws extending fromtemperature control block B or alignment plate 18. As shown in FIG. 1,when temperature control block B is present, slots 38 on each latch 32receive the screws extending from the sides of the temperature controlblock to latch temperature control block B in position, when the latchesare pivoted to the upstanding position. When no temperature controlblock B is present, as in FIG. 2, screws from the alignment plate 18 arereceived in slots 36.

If control of the temperature of the reactor vessels is required, blockB is interposed between pressure plate 14 and the valve block C as shownin FIG. 1. Alignment plate 18 is not used in this configuration. Thetemperature control block is of conventional design, with an array ofvertical reactor vessel receiving wells and internal conduits throughwhich water or other fluid can be pumped to regulate the temperature ofthe reactor vessels.

Valve block C is illustrated in exploded form in FIGS. 4 and 9. Thisblock consists of a top plate 39, a bottom plate 40 and an end cap 42which, when assembled, define a rectangular cavity into which a slide 44is moveably received.

Top plate 39 is provided with openings 46 for screws to secure it tobottom plate 40. It also has openings 48 for screws to secure brackets37 and openings 50 for screws to secure latch pivot blocks 34.

Further, plate 39 has an array of small holes 52 adapted to receive theoutlet tubes 54 which are attached by Leur tip adapters 56 to the bottomoutlet ports of the reactor vessels 10. Outlet tubes of this type arecommercially available from Supelco, Inc., Supelco Park, Belleforte, Pa.10823 as part No. 5-7059 disposable flow control valve liners. One hole52 in plate 39 is provided for each reactor vessel position in reactorblock A.

Bottom plate 40 has corresponding holes 58 for receiving the tubes 54.Holes 58 are of the same number and in the same locations as holes 52 inplate 39. As best seen in FIG. 4, plate 40 has a “U” shapedconfiguration, when viewed from the end. The upper surface of the middlerecessed portion 60 of the plate has eight spaced upstanding ribs 62.Each rib 62 is situated adjacent a different row of holes 58 and, asbest seen in FIG. 9, actually extends a small way over the rim of thehole.

Slide 44 also has an array of holes 64 of the same number and locationas holes 52 and holes 58. However, as best seen in FIG. 9, the top andbottom of each hole 64 is flared outwardly such that conic sections areformed adjacent the top and bottom surfaces of slide 44 so as not to cutor permanently distort tubes 54.

The bottom surface of slide 44 is recessed and provided with eightdownwardly extending ribs 66. Each rib 66 is aligned with a differentrib 62 on bottom plate 40. Between each set of aligned ribs 66, 62 issituated a row of outlet tubes 54. Movement of slide 44 relative tobottom plate 40 causes ribs 66 to move towards ribs 62 such that theoutlet tubes are pinched closed, compare FIGS. 5, 7 and 8.

However, as is best seen in FIGS. 6 and 8, the surface of rib 66 doesnot act directly on the walls of the outlet tubes 54. Instead, it actsthrough a resilient member 68. Member 68 is formed of a sections ofTeflon encapsulated silicone O-ring control commercially available fromLutz Sales, Co., Inc. of 4675 Turnbury Dr., Hanover Park, Ill. 60103.Member 68 deforms as ribs 66 and 62 are moved toward each other andpinches tubes 54 as seen in FIGS. 7 and 8 in a manner which does notcrush or permanently deform the wall of the tube. Thus, the tubereliably returns to its original shape when the slide returns to itsoriginal position, as seen in FIGS. 5 and 6.

As best seen in FIG. 9, which is an enlarged exploded cross-section of aportion of the valve block, the surface of each rib 66 adjacent theresilient member is arcuate to accommodate the curved surface of theresilient member. This curved rib surface insures the proper positioningthe resilient member relative to the outlet tubes.

Each end of bottom plate 40 is provided with a plurality of holes 71each of which is aligned with the space between a different set of ribs62, 66. Holes 71 extend to the exterior surface of the plate and have adiameter slightly larger than that of the resilient members 68. Holes 71permit resilient members 68 to be inserted between the ribs 62, 66 afterthe valve block has been assembled. Holes 71 may be capped or stoppedafter the resilient members are inserted.

Movement of slide 44 relative to plates 40 and 44 is achieved throughthe use of end cap 42. End cap 42 has openings 70 to accommodate screwsfor securing it to bottom and top plates. It also has a central opening71 through which a threaded screw 74 with a knob 76 extends. The innerdiameter of opening 72 is larger then the outer diameter of screw 74such that screw 74 can rotate freely within opening 72. Screw 76 engagesan internally threaded opening 78 in slide 44 such that rotation ofscrew 76 in a clockwise direction causes slide 44 to move relative tobottom plate 40 such that ribs 66 move towards ribs 62 to close the rowsof outlet tubes simultaneously. Rotating screw 76 in thecounter-clockwise direction moves the slide to the extreme openposition, as shown in FIGS. 5 and 6 such that discharge of fluidsthrough outlet tubes 54 is unimpeded. Overtightening of the plates andcrushing or deformation of the tubes is prevented by this structurewhile complete closure of all tubes is insured when the valve is closed.

Situated under valve block C is collection block D. As seen in FIG. 2,block D consists of a locator plate 77 with a large, generallyrectangular central opening 80. Situated below locator plate 77 is avacuum adapter 79. Adapter 79 has a central recess 81 adapted to receivea collection plate, preferably in the form of a 96 well densely packedmicrotiter plate 82 of standard dimension and configuration. For reasonsexplained below, locator plate 77 functions to shift the position ofmicrotiter plate 82 relative to reactor block A. One simple way toaccomplish this is to provide plate 77 in two forms, such that thevacuum adapter is shifted in position, in one form of the locator platerelative to the other. In this way, the position of microtiter plate 82is shifted relative to the reactor vessels simply by substituting oneform of locator plate 77 for the other.

Liquid is drawn downward through the valve block into the microtiterplate using vacuum adapter 79 which is commercially available fromPolyfiltronics, Inc. of 100 Weymouth Street, Rockland, Mass. 02370 whichis sold under part number VAC-003. The Polyfiltronics vacuum adapter ismodified by adding two upstanding locator pins 83 which fit intolocation holes 84 in locator plate 77. Two different locator plates 77are used alternately to align the reactor properly over the microtiterplate for product collection.

Collection block D is situated immediately below valve block C. Thevertical position of collection block D relative to valve block C can bealtered such that different height collection vessels can be utilized inwells 12 of the microtiter plate simply by addition of the appropriatesize spaces (not shown).

Although microtiter plate 82 is capable of receiving 96 collectionvessels in its densely packed well array, reactors designed to acceptmicrocannisters cannot be positioned densely enough to align with all 96wells. Hence, two reactors, of slightly different configuration, arenormally necessary if all 96 wells in the microtiter plate are to beused. However, having different reactor configurations greatlycomplicates the situation and increases the cost.

We overcome this problem by using a single reactor in which 52 possiblereactor vessel positions are provided. Thus, two different sets, of 48vessels positions each, can be selected. By changing the position of themicrotiter plate relative to the reactor block, after selecting thesecond set of 48 vessel positions for use, discharge into all of thewells in the microtiter plate can achieved without using two differentreactor configurations. This is illustrated schematically in FIGS. 11and 12.

These figures show pressure plate 14 of reactor block A and microtiterplate 82 of collection block D. The reactor block A has 52 possiblereactor vessel positions, thirteen columns of four positions each. InFIG. 11, reactor vessels are shown in all but the right most column.Microtiter plate 82 is shown as positioned toward the left of thedrawings, such that reactors in the 48 occupied positions will dischargeinto the 48 collection vessels located in the wells in the microtiterplate designated with a dot.

Referring now to FIG. 12, during the next synthesis set, all of thepositions in the reactor block are selected except the left most column.By utilizing a slightly different locator plate 77, the microtiter plateis shifted to the right, relative to the reactor vessels. Vesselslocated in the positions marked by an “X” discharge into the unused 48collection vessels in the microtiter plate. In this way, the sameapparatus, used a second time after shifting the relative position ofthe microtiter plate, can be used to discharge into all 96 wells of adensely packed microtiter plate.

FIGS. 13 and 14 illustrate the structure of the two forms of locatorplate 77. With the locator plate shown in FIG. 13, the recess 81 invacuum adapter 79 containing microtiter plate 82 is shifted in positionas compared to recess 81 in the adapter shown in FIG. 14. Thus, byselecting the appropriate locator plate form, the microtiter plate willbe aligned with either one or the other set of 48 reactor vessels.

As illustrated in FIG. 8, each reactor vessel 10 is designed so as toreceive a commercially available porus polyethelyene microcannister 88with a radio frequency transmitter tag. These microcannisters are soldby Irori Quantum Microchemistry of of 11025 North Torrey Pines Road,LaJolla, Calif. 92037 and contain the solid phase support. They areporus so as to permit solutions to pass through. They are tagged throughthe use of a microchip with a semiconductor memory which can store anidentification code and other information relating to the constructionof the compound in the cannister. The tags can be interrogated to obtainthe stored information.

The technique for encoding and tracking combinatorial chemical librarieswith this type of microcannister is disclosed in a article entitled“Radiofrequency Encoded Combinatorial Chemistry” by K. C. Nicolaou,Xiao-Yi Xiao, Zahra Parandoosh, Andrew Senyei and Michael P. Nova,published in Angew. Chem. Int. Ed. Engl. 1995, Vol. 34 No. 20 at pages2289-2291; and an article entitled “Radio Frequency Tag EncodedCombinatorial Library Method for the Discovery of Tripeptide-SubstitutedCinnamic Acid Inhibitors of the Protein Tyrosine Phosphatase PTP1B” byEdmund Moran, Sepehr Sarshar, John G. Cargill, Manouchehr M. Shahbaz,Anna Lio, Adnan M. M. Mjalli and Robert Armstrong in J. Am. Chem. Soc.1995, Vol. 117, No. 43 10787-10788.

One of the advantages of the present invention is that reactor vesselslarge enough to receive commercially available microcannisters withradio frequency transmitter tags for tracking of the reactors can beemployed and a single reactor can be used to deposit directly into allof the 96 wells of a standard microtiter plate. This greatly reduces thecomplexity and cost of the system while still permitting automatedtracking.

It should also be noted that although the apparatus of the presentinvention is primarily designed for solid and solution phasecombinatorial synthesis, the reaction vessels could be filled with asorbent and the products could be purified by passing them through thesorbent, a process known as “solid phase extraction”. It is believedthat the present design results in a better solid phase extractionapparatus than anything currently available.

It will now be appreciated that the apparatus of the present inventionconsists of a modular reactor which is simple in design, small in size,light in weight and inexpensive to build and operate. It includes asimplied yet extremely reliable valve means for simultaneouslyregulating the discharge from the reactor vessels without crushing ordeforming the reactor vessel outlet tubes. The reactor vessels aresuitable for receiving porus polyethelene microcannisters with radiofrequency transmitter tags for use in automated encoding. By providing52 reactor vessel positions in the reactor block and a collector blockwhich can shift a standard 96 microtiter plate between two differentrelative positions, a single reactor can be used to discharge into all96 wells of the microtiter plate. Multilevel alignment standoffsfacilitate mounting and alignment of selected components to obtain thedesired configuration. Moreover, the apparatus of the present inventioncan be used to perform the entire synthesis or only to perform thecleavage step in a radio frequency tagged synthesis.

While only a limited number of preferred embodiments of the presentinvention have been disclosed for purposes of illustration, it isobvious that many variations and modifications thereof are possible. Itis intended to cover all of these variations and modifications, whichfall within the scope of the present invention, as recited by thefollowing claims:

We claim:
 1. Apparatus useful for the synthesis of multiple organiccompounds, the apparatus comprising means for receiving an array of Xnumber of individual reactor vessels in at least Y number of differentpositions, wherein Y is a number greater than X, each of said vesselshaving a port connected to an outlet tube through which fluidsdischarge, collection means comprising an array of 2× number ofcollection wells, and means for mounting said collection means belowsaid reactor vessel receiving means in one of two positions relative tosaid reaction vessel receiving means, such that by selecting differentsets of the Y number of positions in which the X number of reactorvessels are received, and changing the collection means position, all 2×number of collection wells in said collection means can receivedischarge from said outlet tubes.
 2. The apparatus of claim 1 whereinsaid collection means comprises a standard 96 well microtiter plate. 3.The apparatus of claim 1 wherein X equals
 48. 4. The apparatus of claim1 wherein Y equal
 52. 5. The apparatus of claim 1 wherein saidcollection means mounting means comprises a locator plate and a vacuumadapter with a collection means receiving opening.
 6. The apparatus ofclaim 5 further comprising means for aligning said adapter in one of twopositions relative to said locator plate.
 7. The apparatus of claim 1wherein each of said reactor vessels comprises a porus polyethlyenemicrocannister with a radio frequency transmitter tag.
 8. The apparatusof claim 1 further comprising valve means interposed between saidreactor vessels and said collection means for simultaneously regulatingthe discharge of fluids through said outlet tubes.